WO2019015112A1 - Composé de benzoimidazole et son procédé de préparation - Google Patents

Composé de benzoimidazole et son procédé de préparation Download PDF

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Publication number
WO2019015112A1
WO2019015112A1 PCT/CN2017/103942 CN2017103942W WO2019015112A1 WO 2019015112 A1 WO2019015112 A1 WO 2019015112A1 CN 2017103942 W CN2017103942 W CN 2017103942W WO 2019015112 A1 WO2019015112 A1 WO 2019015112A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
preparation
reaction
iii
Prior art date
Application number
PCT/CN2017/103942
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English (en)
Chinese (zh)
Inventor
刘雪静
韩迎
杨亮
Original Assignee
鲁南煤化工工程技术研究院
枣庄学院
山东吉田香料股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
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Application filed by 鲁南煤化工工程技术研究院, 枣庄学院, 山东吉田香料股份有限公司 filed Critical 鲁南煤化工工程技术研究院
Priority to US16/485,457 priority Critical patent/US10787420B2/en
Priority to JP2020509138A priority patent/JP6944682B2/ja
Publication of WO2019015112A1 publication Critical patent/WO2019015112A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention belongs to the technical field of organic synthesis, and relates to a benzimidazole compound and a preparation method thereof.
  • the benzimidazole ring system is one of the most ubiquitous core structures used for drug discovery and has been found in many biologically active compounds.
  • Raf kinase inhibitor
  • LCK lymphocyte-specific kinase inhibitor, etc.
  • serotonin receptor phosphodiesterase IV antihistamine Astemizole4 and anti-ulcer omeprazole.
  • o-fluoronitrobenzene compound 8 is another precursor which produces compound 3 by three-step synthesis, the fluorine group of compound 8 is substituted by a primary amine (SN2), the nitro group is reduced to an amine, and then Cyclization with formic acid produces the target compound.
  • SN2 primary amine
  • the present invention provides a benzimidazole compound according to the above-mentioned deficiencies in the prior art, and provides a preparation method thereof, and synthesizes various substituted benzimidazole compounds by SN2 and cyclization reaction, that is, through one-pot reaction.
  • the product is formed by cyclization of the corresponding fluoroaryl-N,N-dimethylformamidine and primary amine via an amine followed by cyclization of the dimethylamine.
  • R 1 is -H, -Cl, alkyl
  • R 2 is -NO 2 , -F, -Cl, Br, -CF 3 , -CN, -CO 2 CH 3 , -CO 2 CH 3 CH 2 ;
  • R 3 is -H, alkyl, -CN, -CF 3 ;
  • R 4 is -H, -Cl, alkyl, cycloalkyl, -CN;
  • R 5 is -H, alkyl, fluoroalkyl, cycloalkyl, arylcyclo, heteroaryl ring;
  • Y is -CH, -CH 2 , -N, -NH, -NH 2 , cycloalkyl.
  • the preparation method of the benzimidazole compound of the invention comprises the following steps:
  • the molar ratio of the compound of the formula (II) to the compound of the formula (III) is 1:1 to 12.
  • R 2 is an electron withdrawing group, and R 2 is preferably -NO 2 , -CF 3 or -CN.
  • the compound of the formula (III) is a primary amine, preferably a primary aliphatic amine, a primary aromatic amine or a primary amine containing a heterocyclic ring.
  • the solvent is DMF, DMA, DMSO, HMPA, THF or dioxane.
  • the reaction temperature is 80 to 220 ° C, and the time is 0.2 to 5 h.
  • the invention has the beneficial effects of synthesizing various substituted benzimidazoles by SN2 and cyclization reaction, that is, by one-pot reaction from the corresponding o-fluoroaryl-N,N-dimethylformamidine and primary amine. Substitution of the fluorine atom by an amine then eliminates the cyclization of dimethylamine to form a product. Compared with the traditional method, the substitution and the ring closure are completed in one pot, the reaction process does not require the use of metal catalysts and/or toxic reagents, the synthesis method has specific selectivity, the reaction product has no isomers, and the process flow is simple and the yield is simple. high.
  • the room temperature is 25 ° C;
  • the stirring method defined by the number of revolutions is a conventional stirring method, and the number of revolutions is 500 to 1000 rpm.
  • reaction mixture was cooled to room temperature, and the reaction mixture was placed in a 50 atmosphere. In a 250 mL separatory funnel of mL water. The mixture was extracted with 3 ⁇ 30 mL of ethyl acetate. Ethyl acetate in the organic phase was removed by rotary distillation, and the mixture was purified by silica gel column chromatography to give the product 1-cyclobutyl-5-nitro-1H-benzo[d]imidazole [1-cyclobutyl-5-nitro- 1H-benzo[d]imidazole] 0.117 g, yield 54%.
  • reaction mixture was poured into a 250 mL separatory funnel containing 50 mL of water. The mixture was extracted with 3 ⁇ 30 mL of ethyl acetate. Ethyl acetate in the organic phase was removed by rotary distillation, and the mixture was purified by silica gel column chromatography to give the product 5-nitro-1-((tetrahydrofuran-2)methyl)-1H-benzo[d]imidazole [5- Nitro-1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole] 0.192 g, yield 78%.
  • reaction mixture was poured into a 250 mL separatory funnel containing 50 mL of water. The mixture was extracted with 3 ⁇ 30 mL of ethyl acetate. Ethyl acetate in the organic phase was removed by rotary evaporation, and the mixture was purified by silica gel column chromatography to give the product 5-nitro-1-((tetrahydrofuran-2)methyl)-1H-benzo[d]imidazole [4- (3-(5-nitro-1H-benzo[d]imidazol-1-yl)propyl)morpholine] 0.246 g, yield 85%.
  • reaction mixture was poured into a 250 mL separatory funnel containing 50 mL of water. The mixture was extracted with 3 ⁇ 30 mL of ethyl acetate. Ethyl acetate in the organic phase was removed by rotary distillation, and the mixture was purified by silica gel column chromatography to afford 4-(3-(6-methyl-5-nitro-1H-benzo[d]imidazole-1). 4-(3-(6-methyl-5-nitro-1H-benzo[d]imidazol-1-yl)propyl)morpholine] 0.216 g, 71% yield.

Abstract

L'invention concerne un composé de benzoimidazole et son procédé de préparation, le procédé de préparation impliquant la synthèse de divers benzoimidazoles substitués au moyen de SN2 et d'une réaction de cyclisation, à savoir, en remplaçant un atome de fluor par une amine dans une réaction monotope, à partir d'aryl-N,N-diméthyl formamidine et d'amine primaire correspondantes, puis en éliminant les produits résultant de la cyclisation de diméthylamine. Le procédé selon l'invention, ne nécessite pas l'utilisation d'un quelconque catalyseur métallique et/ou de tout réactif toxique, et présente une sélectivité spécifique, sans avoir à produire aucun isomère dans le produit de réaction.
PCT/CN2017/103942 2017-07-19 2017-09-28 Composé de benzoimidazole et son procédé de préparation WO2019015112A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US16/485,457 US10787420B2 (en) 2017-07-19 2017-09-28 Benzimidazole compound and preparation method thereof
JP2020509138A JP6944682B2 (ja) 2017-07-19 2017-09-28 ベンゾイミダゾール系化合物の製造方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710589775.0A CN107445899A (zh) 2017-07-19 2017-07-19 一种苯并咪唑类化合物及其制备方法
CN201710589775.0 2017-07-19

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WO2019015112A1 true WO2019015112A1 (fr) 2019-01-24

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Country Link
US (1) US10787420B2 (fr)
JP (1) JP6944682B2 (fr)
CN (1) CN107445899A (fr)
WO (1) WO2019015112A1 (fr)

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CN110759903B (zh) * 2018-07-26 2022-10-28 南开大学 一种噻苯唑的合成新方法
CN108863820B (zh) * 2018-07-30 2021-07-06 枣庄学院 一种取代邻苯二胺的合成方法
CN108640876A (zh) * 2018-08-02 2018-10-12 华侨大学 一种多取代苯并咪唑衍生物及其制备方法
CN109020895B (zh) * 2018-08-07 2020-04-24 枣庄学院 一种金属催化的1-苄胺基取代苯并咪唑的合成方法
CN110256359A (zh) * 2019-06-20 2019-09-20 武汉工程大学 2-氨基苯并咪唑衍生物及其合成和应用

Citations (1)

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CN106866545A (zh) * 2017-03-31 2017-06-20 刘雪静 1‑环烷烃‑5‑硝基‑1h‑苯并[d]咪唑类化合物及其制备方法

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GB1576077A (en) * 1977-04-13 1980-10-01 Roussel Lab Ltd 4,5-dihydro-4-oxophyrrolo(1,2-)-quinoxaline-2-carboxylic acids and derivatives
PT100905A (pt) * 1991-09-30 1994-02-28 Eisai Co Ltd Compostos heterociclicos azotados biciclicos contendo aneis de benzeno, ciclo-hexano ou piridina e de pirimidina, piridina ou imidazol substituidos e composicoes farmaceuticas que os contem
WO2004092181A1 (fr) * 2003-04-11 2004-10-28 Smithkline Beecham Corporation Antagonistes heterocycliques de mchr1
WO2008134354A1 (fr) * 2007-04-27 2008-11-06 Array Biopharma, Inc. Inhibiteur de production de tnf-a
KR101844615B1 (ko) * 2010-07-02 2018-05-14 아스카 세이야쿠 가부시키가이샤 복소 고리 화합물 및 p27Kip1 분해 저해제
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Also Published As

Publication number Publication date
CN107445899A (zh) 2017-12-08
JP2020518661A (ja) 2020-06-25
US10787420B2 (en) 2020-09-29
JP6944682B2 (ja) 2021-10-06
US20200002291A1 (en) 2020-01-02

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